Extended release venlafaxine formulation

ABSTRACT

A controlled release dosage form of venlafaxine that comprises an immediate release pellet and an extended release pellet.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention belongs to the field of pharmaceutical science,and provides an oral controlled release dosage formulation containingvenlafaxine hydrochloride.

2. Description of the Related Art

Venlafaxine hydrochloride is described in U.S. Pat. Nos. 4,535,186;4,761,501 and 6,342,533 which teach the production of venlafaxine andits analogues and are incorporated herein by reference. Venlafaxinehydrochloride is marketed as an antidepressant and for the treatment ofGeneralized Anxiety Disorder. Other uses include prevention of majordepressive disorder relapse, bipolar and manic disorders, post traumaticstress disorder, late luteal phase dysphoric disorder, Gilles de laTourette syndrome, bulimia nervosa or Shy Drager Syndrome, attentiondeficit disorder, Parkinson's disease, epilepsy, cerebral functiondisorders, obesity and weight gain, incontinence, dementia and relateddisorders. It is the preferred antidepressant where weight gain isproblematic, as it is with the selective serotonin reuptake inhibitors(SSRIs). Venlafaxine hydrochloride is a phenylethylamine-derivativechemically unrelated to other currently available antidepressants (e.g.,selective serotonin-reuptake inhibitors, tricyclics, tetracyclics). Itis designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride and has the empirical formula C₁₇H₂₇NO₂ HCL.Venlafaxine has a pKa of 9.4 and has a water solubility of 572 mg/mL.

The neurochemical mechanism of the antidepressant effect is believed tobe potentiation of neurotransmitter activity in the central nervoussystem (CNS). Venlafaxine and its active metabolite,O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronalserotonin and norepinephrine reuptake and weak inhibitors of dopaminereuptake. Venlafaxine does not inhibit monoamine oxidase and has nosignificant affinity for muscarinic, histaminergic or alpha-1 adrenergicreceptors.

The drug is useful in the treatment of depressive affective disorders(e.g. major depression) at dosages of 37.5 to 375 mg daily (dosagesexceeding 375 mg daily of extended release tablets are not recommended).The drug is available in both immediate-release tablets (EFFEXOR®) andextended-release capsules (EFFEXOR® XR). The sustained release capsulesare available in 37.5, 75 and 150 mg capsules administered in a singledose either in the morning or in the evening at approximately the sametime each day. If desired, patients with depression who are undergoingtreatment with a therapeutic dose of conventional tablets may beswitched to the extended-release capsules at the nearest equivalentdaily venlafaxine dose (e.g., 37.5 mg twice daily to a 75 mgextended-release capsule once daily). To minimize gastrointestinalintolerance, it is recommended that the drug be taken with food.However, neither food nor time of administration has been found toeffect bioavailability of venlafaxine or its active metabolite. On thebasis of mass balance studies, at least 92% of a single oral dose ofvenlafaxine is absorbed. The absolute bioavailability is about 45% andplasma protein binding is approximately 30%. Venlafaxine and its activemetabolite, ODV have an elimination half-life (T½) of 5±2 and 11±2hours, respectively.

Administration of the immediate release tablets at a dosage of 75 mgevery twelve hours results in a C_(max), of 225 ng/ml and 290 ng/ml forvenlafaxine and ODV, respectively. T_(max) was 2 hours for venlafaxineand 3 hours for ODV. Administration of the extended release capsulesprovides a slower rate of absorption but the same extent of absorptioncompared with immediate release tablets. A 150 mg dose of the extendedrelease capsules results in a lower C_(max) (150 ng/ml for venlafaxineand 260 ng/ml for ODV) than for immediate release venlafaxine tablets.T_(max) for the extended release capsules was 5.5 hours and 9 hours forvenlafaxine and ODV, respectively. Steady-state concentrations ofvenlafaxine and ODV are attained within three days of oral multiple dosetherapy. Plasma concentrations are altered by hepatic and renalimpairment but unaltered by gender and age. Poor metabolizers, i.e.patients with low CYP2D6 levels have increased levels of venlafaxine andreduced levels of ODV than extensive (“normal”) metabolizers. However,there is no need for dosage adjustment because of similar areas underthe curve (AUCs). The commercially available product is a racemicmixture of the (+) and (−) enantiomers of venlafaxine. All themetabolites are racemic.

Numerous techniques exist in the prior art for preparing sustained orcontrolled release pharmaceutical formulations. Controlled release meansor delivery devices that are well known to those of ordinary skill inthe art, are described, for example in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;5,591,767; 5,120,548; 5,073,543; 5,354,556; 5,733,566 and 6,403,120 thedisclosures of which are incorporated herein by reference.

U.S. Pat. No. 6,048,547 discloses a sustained-release venlafaxinehydrochloride pharmaceutical composition where venlafaxine andmicrocrystalline cellulose are combined with polyethylene oxide (PEO)and compressed into tablets.

Controlled release of the commercially available extended releasevenlafaxine hydrochloride capsules (EFFEXOR®) is achieved by diffusionthrough the coating membrane on the spheroids and is not pH dependent.EFFEXOR® XR is available in a once daily dosage form of venlafaxinewhich contains cellulose, ethylcellulose, gelatin, hydroxypropylmethylcellulose, iron oxide, and titanium dioxide.

The need also exists for a simply and economically producedpharmaceutical preparation which provides a pulsatile delivery system(immediate release followed by sustained release) which attains peakplasma levels, in the manner of an immediate release product, i.eearlier than a controlled release formulation, followed by sustainedrelease over 24 hours. This results in allowing greater flexibility indesigning sustained release profiles and providing improved plasmalevels wherein the maximum plasma concentration (C_(max)) can besubstantially reduced without a concomitant reduction in the area underthe curve (AUC) and without prolongation of the time in which themaximum plasma concentration is obtained (T_(max)). Such a deliverydosage form has a practical application, and it represents a valuablecontribution to the pharmaceutical arts. The present invention providessuch a composition, and offers an efficient and cost effective method ofpreparation.

The present invention was created through efforts to solve the aboveproblems, as well as other problems, and provides a superior pelletformulation of venlafaxine, its pharmaceutically acceptable salts andits active metabolite o-desmethyl venlafaxine (ODV).

Accordingly, it is an object of this invention to provide an oralpharmaceutical formulation of venlafaxine hydrochloride or its activemetabolite (ODV) suitable for once daily administration that obtains itsmaximum plasma levels in less than 4 hours.

It is a further object of the present invention to provide a once a daypharmaceutical formulation that will provide 24 hour control of symptomsof depression or Generalized Anxiety Disorder.

The present invention relates to a new sustained release venlafaxine orits active metabolite pharmaceutical composition producing novel bloodplasma levels which is not disclosed in, not rendered obvious by,previous patents nor elsewhere in the art. Other objects, features andadvantages of the invention are not taught in the prior art, but will bemore apparent to those versed in the art from the followingspecification, taken in conjunction with the drawings.

SUMMARY OF THE INVENTION

The active ingredients of this invention include venlafaxine, its activemetabolite (ODV) and their analogs. For the purposes of this disclosure,and the claims that follow, the use of venlafaxine is understood toinclude the free base and pharmaceutically acceptable salt forms ofvenlafaxine, the racemate and its individual enantiomers, andvenlafaxine analogs, both as racemates and as their individualenantiomers.

A preferred embodiment of the present invention involves the applicationof a venlafaxine and a binder onto inert spheres to form an immediaterelease pellet. Extended-release pellets are then formed by coating theimmediate release pellets with a water-insoluble film forming polymer.The release rate of the drug from the extended release pellet iscontrolled by the thickness of the coating and the composition of thecoating. The final formulation comprises a mixture of immediate releaseand extended release pellets. The venlafaxine hydrochloride releaseprofile of the final formulation is controlled by varying the amounts ofnon-coated immediate release pellets and extended-release pellets. Theimmediate release and extended release pellets may be placed into acapsule or formed into a tablet using conventional tablet formingtechniques.

Generally, the weight ratio of the immediate release pellets to theextended release pellets will be from about 90:10 to about 10:90,although a weight ratio of from about 20:80 to about 80:20 is preferred.The most preferred dosage form comprises about 25-50 weight percent ofimmediate release pellets and about 50-75 weight percent extendedrelease pellets.

In a preferred embodiment, the dosage form will be administered once aday, ideally with or after a meal, and provide therapeutic levels of thedrug throughout the day with peak plasma levels being obtained in lessthan five hours, preferably between 1-4 hours and most preferablybetween 2-3 hours, after administration. The usual dosage range is75-375 mg.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a controlled release venlafaxine formulation fororal administration, said formulation comprising:

-   -   (1) an immediate release pellet comprising:        -   (a) venlafaxine, its active metabolite, their isomers, or            pharmaceutically acceptable salts thereof,        -   (b) an inert pellet as a starting material; and        -   (c) a binder; and    -   (2) extended release pellet comprising:        -   (i) a core comprising:            -   (a) venlafaxine, its active metabolite, their isomers,                or pharmaceutically acceptable salts thereof;            -   (b) an inert pellet as a starting material; and            -   (c) a binder; and        -   (ii) a coating comprising:            -   (a) a water insoluble film-forming polymer; and        -   (iii) optionally a second coating comprising:            -   (a) a second film forming water insoluble polymer;

The formulation of the present invention is preferably based on activepellets having a core comprising any of the commonly known pelletstarting material such as starch, sugar, microcrystalline cellulose,glass, vegetable gums or waxes having a diameter ranging from about 15to about 60 mesh, preferably from about 20 to about 40 mesh. Thepreferred pellet starting material is sugar spheres, NF containing notless than about 62.5 percent and not more than about 91.5 percent ofsucrose. The primary characteristic of the inert pellet is that it doesnot adversely react with venlafaxine, the other possible excipients inthe pellet or the patient who will ultimately ingest the pellet.Further, the spheres should have consistent bulk density, lowfriability, and low dust generation properties.

An active drug layer is applied onto the inert pellets by spraying asuspension or solution comprising venlafaxine and a binder. The binderpreferably is a film-forming polymer that possesses high adhesivity andan appropriate viscosity, to assure good adhesion between the sugarcores and venlafaxine particles. The binding agents employed can be anyfilm-forming binding agent commonly known in the art such as celluloseethers (e.g. ethyl cellulose), polyoxides, polyacrylates, polyethylene,polypropylene, polyurethane, hydroxypropyl methylcellulose,hydroxypropyl cellulose and polyvinylpyrrolidone. Mixtures of theaforementioned binding agents may also be used. In a preferredembodiment of the present invention, the film-forming binding agent is awater insoluble polymer such as ethylcellulose. In a second embodimentof the invention, a film-forming water soluble binder may be combinedwith the water insoluble binder. The preferred film-forming watersoluble binding agent is polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose.

The active pellets of the present invention will preferably comprise thefollowing ingredients: INGREDIENT PREFERRED MOST PREFERRED venlafaxine30-80% 45-70% binder  1-20%  2-15% starting pellets 20-70% 30-50%

All the percentages in the above table are based on the total weight ofthe active pellets. If a combination of water insoluble and watersoluble binders are used the water insoluble binder should be less than50% of the total binder, preferably less than 40% and most preferredless than 35%.

The active drug layer is applied onto the inert pellet using any of thelayering techniques known in the industry such as fluidized bed coating,rotor granulation or pan coating. A preferred method for applying activelayer onto the inert pellet is the classic fluidized bed coating device,which consists simply of a vertical cylinder with an air-permeablebottom. The cylinder is charged with the inert pellets to be coated,sufficient volume of air is drawn through the bottom of the cylinder tosuspend the mass of inert pellets, and the liquid to be applied issprayed onto the inert pellets. The temperature of the fluidized air isbalanced against the spray rate to maintain the inert pellets at thedesired level of moisture and stickiness while the active coating isbuilt up.

Once the active drug layer is applied onto the inert pellet, the productis referred to as the immediate release pellet or active pellet.

The immediate release pellets are coated with an extended releasecoating composition comprising a water insoluble polymer (preferably apolymethacrylate), and conventional processing aids such as asurfactant, an antisticking agent, and a plasticizer to form an extendedrelease coating on the active pellets. The release of the drug from theextended release pellet is primarily controlled by the diffusion of thedrug through the polymer coating. The extended release pelletspreferably comprise from about 20 to about 90 weight percent of thetotal pellets in the final dosage formulation, preferably from about 40to about 80 weight percent, and most preferably from about 60 to about75 wt %.

The water insoluble polymer is preferably a polymethacrylate,methacrylic acid copolymers, methacrylate ester copolymers, acrylic acidor mixtures thereof. Eudragit® NE 30D, was found to be a suitablepolymer for the present invention. Other preferred water insolublepolymers are cellulose esters, cellulose ethers, or celluloseester-ethers such as ethyl cellulose, cellulose acylate, cellulosedeacylate, cellulose triacylate, cellulose acetate, cellulose acetatebutyrate, cellulose diacetate, cellulose triacetate, mono- di- andtri-cellulose arylates, and the like. Additional water insolublepolymers for forming the outer coating comprise cellulose acetaldehydedimethyl acetate, cellulose acetate ethylcarbamate, cellulose acetatemethylcarbonate, cellulose dimethylaminoacetate, semipermeablepolyamide, polyvinyl acetate, semipermeable polyurethanes, semipermeablesulfonated polystyrenes, crosslinked selectively semipermeable polymersformed by the coprecipitation of an anion and a cation.

The water-insoluble polymer should comprises about 40 to about 99percent of the extended-release coating, preferably about 50 to about 90percent and most preferably about 60 to about 85 percent.

In an alternative embodiment of the present invention, two extendedrelease coatings are applied to the immediate release pellets. The firstextended release coating comprises a polymethacrylate, methacrylic acidcopolymer, methacrylate ester copolymer, acrylic acid or mixturesthereof and the second extended release coating comprises a celluloseester, a cellulose ether, or a cellulose ester-ether.

The extended release coatings applied to the immediate release pelletsmay optionally include a surfactant. The surfactant is selected fromanionic, cationic, amphoteric and nonionic surfactants, includingdialkyl sodium sulfosuccinate, polyoxyethylene glycerol, polyoxyethylenesteryl ether, propoxy-ethoxy copolymer, polyoxyethylene fatty alcoholester, polyoxyethylene sorbitan fatty acid esters, ethoxylatedhydrogenated castor oil and butoxylated hydrogenated castor oil. Thepreferred surfactant is polysorbate 80 (Tween 80). If a surfactant isemployed in the extended release coating it should be used in aconcentration of 30 weight percent or less based upon the total weightof the extended release coating. The preferred amount of surfactant ispreferably about 0.01 to about 20 percent and most preferably about 0.1to about 10 percent of the extended-release coating.

The extended release coating may also optionally include ananti-sticking agent. The anti-sticking agent can be chosen from any ofthe known agents such as those selected from the group consisting of analkaline earth metal stearate, glyceryl monostearate or talc. Thepreferred anti-sticking agents are talc and magnesium stearate. If usedin the extended release coating, the anti-sticking agent should compriseabout 1 to about 15 percent, and most preferably about 2 to about 10percent, based on the total weight of the extended-release coating. Acombination of anti-sticking agents such as talc and magnesium stearatemay be used in the present invention.

The extended release coatings may also optionally include a plasticizerto reduce the brittleness of the coatings. Plasticizers which may beused include any of those known to those skilled in the art which arecompatible with cellulose acetate, including but not limited to,acetyltributyl citrate, triacetin, acetyltriethyl citrate,dioctylphthalate, dibutylphthalate, triethyl citrate, tributylcitrate,polyethylene glycol, propylene glycol and mixtures thereof. Thepreferred plasticizer is triacetin. If a plasticizer is used in theextended release coating, the amount used should range from about 0.01to about 30 percent based on the total weight of the extended-releasecoating, preferably about 0.1 to about 15 percent of theextended-release coating.

The extended release coatings are applied to the active pellets byforming a solution or suspension of the respective polymer andprocessing aids in a solvent such as acetone, isopropyl alcohol, orwater and employing any of the application techniques known to thoseskilled in the art, such as fluidized bed coating, rotor granulation orpan coating. The preferred method is the fluidized bed. The choice ofduration of mixing, the apparatus, the screens and other operatingconditions is a matter for the normal skill and judgment of a personskilled in the art. Extended release pellets are dried in an oven atabout 60° C. for about 40 hours.

A second coating may be added to the extended release pellets comprisinga water insoluble polymer, an antisticking agent and a plasticizer.Examples of these excipients are listed above. Preferably the waterinsoluble polymer is cellulose acetate, the antisticking agent is talcand the plasticizer is triacetin. The coating is applied using the sameapparatus and procedure used to prepare the extended release pelletsabove.

If the second extended release coating is employed it should comprisesabout 2-10 weight percent, preferably 3-7 weight percent of the extendedrelease pellet and the first extended release coating should compriseabout 10-50 weight percent, preferably, 15-40 weight percent of thetotal weight of the extended release pellets.

The final dosage form contains a mixture or blend of immediate releasepellets and extended release pellets that are placed into a gelatincapsule. By varying the ratios of the two pellet, novel dissolutionprofiles and plasma profiles may be obtained. Alternatively, theimmediate and extended release pellets can be further mixed withconventional tablet excipients and formed into tablets.

The drug is released from the final dosage form in a pulsatile mannerwith a portion released immediately and a portion released slowly andsteadily for a prolonged period of up to 24 hours. The rate ofvenlafaxine release was determined according to the USP 26 standardprocedures employing a Type 2 Apparatus, at 50 rpm with distilled waterat 37° C. The controlled release dosage forms prepared according to thepresent invention should exhibit the following dissolution profile whentested according to the above described procedure: Time (hours)Preferred Most Preferred 1  0-55% 20-40% 4 20-60% 30-50% 8 25-80% 35-70%12 NLT 30% NLT 35% 24 NLT 50% NLT 60%NLT = not less than

The following examples illustrate the present invention and are notintended to limit the scope of the present invention.

EXAMPLE 1

A controlled release oral venlafaxine HCl dosage form in accordance withthe present invention is prepared by first forming immediate releasepellets having the following composition:

I Immediate Release Pellets % Total Weight venlafaxine HCL 60% sugarsphere 30/35 35% ethylcellulose (EC 10 Cps)  5%

Immediate release pellets of venlafaxine HCl are formed by dissolvingethylcellulose (EC 10 cps) in isopropyl alcohol and suspendingvenlafaxine HCl in the ethylcellulose solution to make a suspension of25% solid content. The active drug suspension is then sprayed onto thesugar spheres 30/35 in a fluidized bed processor with a Wuster insertuntil the seeds are uniformly coated with the desired drug potency. Theimmediate release pellets are then dried in a fluidized bed processoruntil the moisture level, as measured by the loss on drying, is below2%. The immediate release pellets are then passed through a 14 meshscreen and a 25 mesh screen and pellets are collected that are sizedbetween 14 mesh and 25 mesh.

II. Extended Release Pellets

About two third of the immediate-release pellets from Step I above areused to prepare extended release pellets with the following composition:immediate release pellets (from Step I above) 63.38% talc  4.58%magnesium stearate  4.58% Tween 80  0.05% Eudragit NE 30D 27.41%

First the talc is suspended in purified water. In a separate vessel,Tween 80 is added to isopropyl alcohol followed by magnesium stearate.The talc suspension is added to the magnesium stearate suspension. Thetalc-magnesium stearate suspension is then added to the Eudragit NE 30Dsuspension. The suspension is then sprayed onto the immediate releasepellets in a fluidized bed processor with a Wuster insert to form theextended release pellets having approximately a 36% coating level. Theextended release pellets are dried in the fluidized bed processor untilthe LOD (loss on drying) is less than 1%. The extended release pelletsare mixed with 2% (w/w) talc for 10 minutes and subsequently cured at60° C.±5° C. for about 40 hours. The cured pellets are passed through 14and 25 mesh screens. The pellets retained on the 25 mesh screen are usedin the formulation.

The immediate release pellets prepared in step I and extended releasepellets prepared in step II are encapsulated. The final encapsulateddosage form contains 150 mg of venlafaxine base with the immediaterelease pellets comprising 55.5 mg of venlafaxine base and the extendedrelease-pellets comprising 94.5 mg of venlafaxine base.

The resulting venlafaxine capsules were then tested according to the USP26 dissolution test (type 2) at 50 rpm, at 37° C. in distilled water andfound to have the following release profile: TABLE 1 Time (hours) %Released 0.25 37 0.5 37 1 37 2 37 4 37 6 37 8 38 12 42 20 60 24 68

The venlafaxine capsules produced in Example 1 were administered tohuman patients. Venlafaxine was first detected in the plasma at about 15minutes after administration, and showed sustained release over 24hours. The testing involved two groups of randomly selected patientsthat received either the venlafaxine formulation prepared in thisExample or EFFEXOR® XR 150 mg in an open, randomized crossover singledose fasting study. Blood samples were collected over a 72 hour periodand analyzed for venlafaxine concentrations. EFFEXOR® XR was thereference product and is a commercially available pharmaceutical productcontaining venlafaxine HCl. The results are given in Table 2. TABLE 2Test Mean Ref. Mean G-Mean Ratio FASTING (N = 5) C_(max) (ng/ml) 50.81067.799 0.718 AUC_(TLQC) (ng hr/ml) 633.699 882.542 0.749 T_(max) (hr)1.827 6.359 0.287 FED (N = 5) C_(max) (ng/ml) 83.92 96.44 0.866AUC_(TLQC) (ng hr/ml) 1476.69 1458.26 1.01 T_(max) (hr) 3.292 6.4030.514

EXAMPLE 2

A controlled release venlafaxine formulation in accordance with thepresent invention is prepared by first forming immediate release pelletshaving the following composition:

I. Immediate Release Pellets % Total Weight venlafaxine hydrochloride60.0 sugar spheres 34.0 PVP (K-30) 4.0 EC 10 cps 2.0

Immediate release pellets of venlafaxine HCl are formed by dissolvingethylcellulose (EC 10 cps) and the PVP (K-30) in isopropyl alcohol andsuspending venlafaxine HCl in the ethylcellulose/PVP solution to make asuspension of 30% solid content. The active drug suspension is thensprayed onto the sugar spheres 30/35 in a fluidized bed processor with aWuster insert until the seeds are uniformly coated with the desired drugpotency. The immediate release pellets are then dried in a fluidized bedprocessor until the moisture level, as measured by the loss on drying,is below 2%. The immediate release pellets are then passed through a 14mesh screen and a 25 mesh screen and pellets are collected that aresized between 14 mesh and 25 mesh.

II. Extended Release Pellets

Extended release pellets in accordance with the present invention areprepared using a portion of the immediate release pellets prepared inStep I above. The extended release pellets have the followingcomposition: % TOTAL WT. immediate release pellets (Step I) 79.37 talc2.58 magnesium stearate 2.58 tween 80 0.03 Eudragit NE 30D 15.44

The extended release pellets are prepared according to the proceduredescribed in Example 1 except the immediate release beads are coateduntil a 22% theoretical coating level is obtained.

The strength of the final encapsulated product is 150 mg of venlafaxinebase with the immediate release pellets comprising 55.5 mg ofvenlafaxine base and the extended release pellets comprising 94.5 mg ofvenlafaxine base.

The resulting venlafaxine capsules were then tested according to the USP26 dissolution test (type 2), at 50 rpm, at 370 C, in distilled waterand found to have the following release profile: TABLE 3 Time (hours) %Released 0.25 35 0.50 36 1 36 2 36 4 37 8 63 12 86 20 99 24 101

The venlafaxine capsules produced in this Example were administered tohuman patients. Venlafaxine showed a sustained release over 24 hours.The results of the in vivo provided are given in Tables 4 and 5. TABLE 4FASTING (N = 5) Test Mean Ref. Mean G-Mean Ratio C_(max) (ng/ml) 108.3089.32 1.21 AUC_(TLQC) (ng hr/ml) 1486.68 1211.56 1.23 T_(max) (hr) 4.4586.00 0.743

TABLE 5 FED (N = 6) G-Mean Test Mean Ref. Mean Ratio C_(max) (ng/ml)119.06 94.74 1.26 AUC_(TLQC) (ng hr/ml) 1624.90 1358.30 1.20 T_(max)(hr) 5.00 4.83 1.03

EXAMPLE 3

A controlled release venlafaxine formulation in accordance with thepresent invention is prepared by first forming immediate release pelletshaving the following composition:

I. Immediate Release Pellets I. IMMEDIATE RELEASE PELLETS % Total Weightvenlafaxine hydrochloride 60.0 sugar spheres 35.0 EC 10 cps 5.0

The immediate release pellets are prepared according to the proceduredescribed in Example 1.

II. Extended Release Pellets

Extended release pellets in accordance with the present invention areprepared using a portion of the immediate release pellets prepared inStep I above. The extended release pellets have the followingcomposition: % TOTAL WT. immediate release pellets (Step I) 71.00 talc3.62 magnesium stearate 3.62 tween 80 0.04 Eudragit NE 30D 21.71

The extended release pellets are prepared according to the proceduredescribed in Example 1.

A second extended release coating is applied to the extended releasepellets prepared in step II. The second coated extended release pelletsthen have the following composition:

III. Second Coating % TOTAL WT. venlafaxine extended pellets (Step II)96.0 cellulose acetate 2.42 talc 1.21 triacetin 0.36

The second coating is applied to the extended release pellets preparedin Step II using the same apparatus and procedure used to prepare theextended release pellet. The pellets sized between #14 and #25 mesh arecollected.

108 mg of the immediate release pellets and 258.2 mg of the extendedrelease pellets are then encapsulated to give a final dosage form thatcontains approximately 150 mg of venlafaxine base.

The resulting venlafaxine capsules were then tested according to the USP26 dissolution test (type 2), at 50 rpm, at 37° C., in distilled waterand found to have the following release profile: TABLE 6 Time (hours) %Released 0.25 36 0.50 37 1 37 2 38 4 39 6 44 8 51 12 65 20 83 24 89

The venlafaxine capsules produced in this Example were administered tohuman patients according to the procedure described in Example 1. Theresults provided given in Table 7. TABLE 7 FASTING (N = 8) Test Mean(CV)Ref. Mean(CV) G-Mean Ratio C_(max) (ng/ml) 61.962 67.799 0.914 AUC₀₋₄₈(ng hr/ml) 788.170 882.542 0.893 T_(max) (hr) 1.938 6.359 0.305

While certain preferred and alternative embodiments of the inventionhave been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, this specification is intended to coverall embodiments of the invention and modifications thereof which do notdepart from the spirit and scope of the invention.

1. A controlled release composition for oral administration, comprising:(1) an immediate release pellet comprising: (a) venlafaxine, its activemetabolite, isomers, or a pharmaceutically acceptable salts thereof; (b)an inert pellet; and (c) a binder; (2) an extended release pelletcomprising: (i) a core comprising: (a) venlafaxine, its activemetabolite, isomers, or a pharmaceutically acceptable salts thereof; (b)an inert pellet; and (c) a binder; (ii) a coating surrounding the corecomprising: (a) a water-insoluble polymer.
 2. The controlled releasecomposition according to claim 1 wherein the maximum plasmaconcentration in humans of venlafaxine is obtained in less than fourhours.
 3. The controlled release composition according to claim 2wherein the maximum plasma concentration of venlafaxine is obtained inabout one to about four hours.
 4. The controlled release compositionaccording to claim 1 wherein (1) the immediate release pellet comprises:(a) 30-80% of venlafaxine, its active metabolite, isomer, orpharmaceutically acceptable salt thereof; (b) 20-70% of an inert pellet;and (c) 1-20% of a binder; and (2) the extended release pelletcomprises: (i) the core comprising: (a) 30-80% of venlafaxine, itsactive metabolite, isomer, or a pharmaceutically acceptable saltsthereof; (b) 20-70% of an inert pellet; and (c) 1-20% of a binder; (ii)the coating and optionally the second coating if employed comprising;(a) 40-99% of a water insoluble polymer; (b) 0-20% of a surfactant; (c)0-15% of an antisticking agent; and (d) 0-30% of a plasticizer.
 5. Thecontrolled release composition according to claim 4 wherein (1) theimmediate release pellet comprises: (a) 45-70% of venlafaxine, itsactive metabolite, isomer, or a pharmaceutically acceptable salts; (b)30-50% of an inert pellet; and (c) 2-15% of a binder; and (2) theextended release pellet comprises: (i) the core comprising: (a) 50-70%of venlafaxine, its active metabolite, isomer, or a pharmaceuticallyacceptable salt; (b) 30-50% of an inert pellet; and (c) 2-15% of abinder; and (ii) the coating and optionally the second coating ifemployed comprising: (a) 50-90% of a water insoluble polymer; (b)0.1-10% of a surfactant; (c) 2-10% of an antisticking agent; and (d)0.1-15% of a plasticizer.
 6. The controlled release compositionaccording to claim 1, in which said inert pellet is selected from thegroup consisting of starch spheres, sugar, microcrystalline cellulose,glass, vegetable gums, and waxes, said inert pellet starting materialhaving a diameter ranging from about 15 to about 60 mesh.
 7. Thecontrolled release composition according to claim 1, wherein theextended release pellets comprise from about 40-80% of the total drug.8. The controlled release composition according to claim 7, wherein theextended release pellets comprise from 60-75% of the total drug.
 9. Thecontrolled release composition according to claim 1, wherein the binderis selected from the group consisting of cellulose esters, celluloseethers, polyoxides, polyacrylates, polyethylene, polypropylene,polyurethane, hydroxypropyl methylcellulose, hydroxypropyl cellulose,polyvinylpyrrolidone and mixtures of the foregoing.
 10. The controlledrelease composition according to claim 1, wherein the binder is a waterinsoluble polymer.
 11. The controlled release composition according toclaim 10, wherein the binder is ethylcellulose.
 12. The controlledrelease composition according to claim 1 wherein the binder is a mixtureof water insoluble polymers and water soluble polymers.
 13. Thecontrolled release composition according to claim 12 wherein the binderis a mixture of ethylcellulose and poylvinyl pyrrolidone.
 14. Thecontrolled release composition according to claim 1, wherein thewater-insoluble polymer is selected from the group consisting ofpolymethacrylate, methacrylic acid copolymers, methacrylate estercopolymers, acrylic acid, cellulose esters, a cellulose ethers,cellulose ester-ethers or mixtures thereof.
 15. The controlled releasecomposition according to claim 1 wherein the water insoluble polymer ispolymethacrylate, methacrylic acid copolymers, methacrylate estercopolymers, acrylic acid.
 16. The controlled release compositionaccording to claim 1 wherein the second coating is not optional.
 17. Thecontrolled release composition according to claim 1 wherein the firstwater insoluble polymer is a polymethacrylate, methacrylic acidcopolymers, methacrylate ester copolymers or acrylic acid.
 18. Thecontrolled release composition according to claim 1 that exhibits thefollowing dissolution profile when tested according to USP 26 with aType 2 Apparatus at 50 rpm in distilled water at 37° C.: 0-55% of thevenlafaxine is released after one hour; 20-60% of the venlafaxine isreleased after four hours; 25-80% of the venlafaxine is released aftereight hours; and not less than 50% of the venlafaxine is released aftertwenty four hours.
 19. The controlled release composition according toclaim 18 having the following dissolution profile when tested accordingto USP 26 with a Type 2 Apparatus at 50 rpm in distilled water at 37°C.: 10-40% of the venlafaxine is released after one hour; 30-50% of thevenlafaxine is released after four hours; 35-70% of the venlafaxine isreleased after eight hours; and not less than 60% of the venlafaxine isreleased after twenty-four hours.
 20. A method for providing atherapeutic blood plasma concentration of venlafaxine over a twenty fourhour period which comprises administering orally to a patient in needthereof, a controlled release formulation that provides a peak plasmablood level of venlafaxine obtained in less than four hours.
 21. Themethod according to claim 20 wherein peak plasma blood level ofvenlafaxine is obtained in about one to about four hours.
 22. Thecontrolled release composition according to claim 1, wherein saidcomposition is in the form of a tablet or capsule.
 23. A controlledrelease composition consisting essentially of: (1) an immediate releasepellet consisting essentially of: (a) 30-80% of venlafaxine, its activemetabolite, isomer, or pharmaceutically acceptable salt thereof; (b)20-70% of an inert pellet; and (c) 1-20% of a binder; and (2) anextended release pellet consisting essentially of: (i) a core consistingessentially of: (a) 30-80% of venlafaxine, its active metabolite,isomer, or a pharmaceutically acceptable salts thereof; (b) 20-70% of aninert pellet; and (c) 1-20% of a binder; (ii) a coating consistingessentially of: (a) 40-99% of a water insoluble polymer; (b) 0-30% of asurfactant; (c) 0-15% of an antisticking agent; and (d) 0-30% of aplasticizer; wherein the peak plasma concentration of the venlafaxine isobtained in less than four hours and the extended release pelletscomprises about 40-80% of the total drug.
 24. The controlled releasecomposition according to claim 23 wherein (1) the immediate releasepellet consist essentially of: (a) 45-70% of venlafaxine, its activemetabolite, isomer, or a pharmaceutically acceptable salts thereof; (b)30-50% of an inert pellet; and (c) 2-15% of a binder; and (2) theextended release pellet consist essentially of: (i) a core consistingessentially of: (a) 45-70% of venlafaxine, its active metabolite,isomer, or a pharmaceutically acceptable salt thereof; (b) 30-50% of aninert pellet; and (c) 2-15% of a binder; and (ii) a coating consistingessentially of: (a) 50-90% of a water insoluble polymer; (b) 0.1-10% ofa surfactant; (c) 2-10% of an antisticking agent; and (d) 0.1-15% of aplasticizer; wherein the peak plasma concentration of the venlafaxine isobtained in less than five hours and the extended release pelletscomprises about 60-75% of the total drug.
 25. The controlled releasecomposition according to claim 24 wherein the maximum plasmaconcentration of venlafaxine is obtained in less than four hours. 26.The controlled release composition according to claim 25 wherein themaximum plasma concentration of venlafaxine is obtained in about one toabout four hours.
 27. A controlled release composition for oraladministration, according to claim 1, comprising: (1) an immediaterelease pellet comprising: (a) venlafaxine, its active metabolite,isomers, or a pharmaceutically acceptable salts thereof; (b) an inertpellet; and (c) a binder; (2) an extended release pellet comprising: (i)a core comprising: (a) venlafaxine, its active metabolite, isomers, or apharmaceutically acceptable salts thereof; (b) an inert pellet; and (c)a binder; (ii) a coating surrounding the core comprising: (a) awater-insoluble polymer; (iii) a second coating comprising (a) awater-insoluble polymer; (b) a antisticking agent; and (c) aplasticizer.
 28. The controlled release composition according to claim27, wherein (1) the immediate release pellet comprises: (a) 30-80% ofvenlafaxine, its active metabolite, isomer, or pharmaceuticallyacceptable salt thereof; (b) 20-70% of an inert pellet; and (c) 1-20% ofa binder; and (2) the extended release pellet comprises: (i) the corecomprising: (a) 30-80% of venlafaxine, its active metabolite, isomer, ora pharmaceutically acceptable salts thereof; (b) 20-70% of an inertpellet; and (c) 1-20% of a binder; (ii) a first coating comprising; (a)40-99% of a water insoluble polymer; (b) 0-20% of a surfactant; (c)0-15% of an antisticking agent; and (d) 0-30% of a plasticizer; (iii) asecond coating comprising; (a) 30-90% of a water-insoluble polymer; (b)5-50% of a antisticking agent; and (c) 1-20% of a plasticizer.
 29. Thecontrolled release composition according to claim 28 wherein (1) theimmediate release pellet comprises: (a) 45-70% of venlafaxine, itsactive metabolite, isomer, or a pharmaceutically acceptable salts; (b)30-50% of an inert pellet; and (c) 2-15% of a binder; and (2) theextended release pellet comprises: (i) the core comprising: (a) 50-70%of venlafaxine, its active metabolite, isomer, or a pharmaceuticallyacceptable salt; (b) 30-50% of an inert pellet; and (c) 2-15% of abinder; and (ii) the first coating comprising: (a) 50-90% of a waterinsoluble polymer; (b) 0.1-10% of a surfactant; (c) 2-10% of anantisticking agent; and (d) 0.1-15% of a plasticizer; (iii) a secondcoating comprising (a) 45-70% of a water-insoluble polymer; (b) 20-40%of a antisticking agent; and (c) 5-15% of a plasticizer.
 30. Acontrolled release composition, consisting essentially of: (1) animmediate release pellet consisting essentially of: (a) 30-80% ofvenlafaxine, its active metabolite, isomer, or pharmaceuticallyacceptable salt thereof; (b) 20-70% of an inert pellet; and (c) 1-20% ofa binder; and (2) an extended release pellet consisting essentially of:(i) a core consisting essentially of: (a) 30-80% of venlafaxine, itsactive metabolite, isomer, or a pharmaceutically acceptable saltsthereof; (b) 20-70% of an inert pellet; and (c) 1-20% of a binder; (ii)a coating consisting essentially of: (a) 40-99% of a water insolublepolymer; (b) 0-30% of a surfactant; (c) 0-15% of an antisticking agent;and (d) 0-30% of a plasticizer; and (iii) a second coating comprising;(a) 30-90% of a water-insoluble polymer; (b) 5-50% of a antistickingagent; and (c) 1-20% of a plasticizer. wherein the peak plasmaconcentration of the venlafaxine is obtained in less than four hours andthe extended release pellets comprises about 40-80% of the total drug.31. The controlled release composition according to claim 30 wherein themaximum plasma concentration of venlafaxine is obtained in about one toabout four hours.
 32. The controlled release composition according toclaim 30 wherein (1) the immediate release pellet consist essentiallyof: (a) 45-70% of venlafaxine, its active metabolite, isomer, or apharmaceutically acceptable salts thereof; (b) 30-50% of an inertpellet; and (c) 2-15% of a binder; and (2) the extended release pelletconsist essentially of: (i) a core consisting essentially of: (a) 45-70%of venlafaxine, its active metabolite, isomer, or a pharmaceuticallyacceptable salt thereof; (b) 30-50% of an inert pellet; and (c) 2-15% ofa binder; and (ii) a first coating consisting essentially of: (a) 50-90%of a water insoluble polymer; (b) 0.1-10% of a surfactant; (c) 2-10% ofan antisticking agent; and (d) 0.1-15% of a plasticizer; and (iii) asecond coating comprising; (a) 45-70% of a water-insoluble polymer; (b)20-40% of a dusting agent; and (c) 5-15% of a plasticizer. wherein thepeak plasma concentration of the venlafaxine is obtained in less thanfour hours and the extended release pellets comprises about 60-75% ofthe total drug.